Throughout this application, various publications are referenced by author and date. Full citations for these publications may be found listed alphabetically at the end of the specification immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.
The development of reliable asymmetric catalysts for organic synthesis has had an enormous impact on the ability of chemists to assemble relatively small enantiopure building blocks for pharmaceutical research and natural products synthesis. (Noyori, 1994). Many such processes are now amenable to industrial-scale production. By contrast, similarly reliable catalytic methods for stereoselective carbon--carbon bond formation during the middle and late stages of a relatively complex synthetic enterprise are perhaps not as developed, with the consequence that many worthy pharmaceutically relevant targets cannot practically be synthesized in large amounts. This is unacceptable. The recently developed HIV protease inhibitors provide a striking example of the increasing level of structural complexity that may be required of synthetic pharmaceuticals. As increasingly complex pharmaceutical agents are designed, synthetic chemists must provide the necessary tools for their efficient synthesis during the discovery and production stages. Indeed, the availability of new synthetic methods can open up new avenues in pharmaceutical research.
The recent resurgence of drug-resistant bacterial and fungal infections demands the renewed efforts of medicinal and synthetic chemists alike in antibiotics research. (Sternberg, 1994). The polyene macrolide antibiotics (e.g. amphotericin B and mycoticin A are a rich natural source of antibiotic lead structures. (Rychnovsky, 1995). Indeed, amphotericin B, while far from ideal, is still one of the most effective clinical anti-fungal agents known. (Belard, 1986; Hartsel, et al., 1993). This general type of structure could form the basis of the next generation of anti-fungal agents. The recent discovery of leucascandrolide A (Nakata, 1990) a powerfully anti-fungal natural product, supports this notion. While this latter compound is not a polyene macrolide, it does share one primary structural feature usually found in the polyene macrolides: an extended (1,3,5 . . . ) polyol-derived segment. Thus, the development of general methods for the synthesis of such segments that are catalytic and require only inexpensive reagents is a worthy goal whose attainment could have a wide-ranging effect on both the discovery and production stages of pharmaceutical research.
Many methods have been developed for the stereoselective synthesis of (1,3,5 . . . ) polyol chains. (Rychnovsky, 1995; Oishi and Nakata, 1990). Recently successful and generally applicable methods for polyol synthesis based on dithiane-epoxide and cyanohydrin-alkyl halide couplings respectively have been developed. (Nicolaou, et al., 1988; Kennedy et al., 1988; Poss, et al., 1993; Mori, et al., 1994; Rychnovsky, et al., 1994). In devising a new approach based on catalytic processes, the present invention is focused on the .beta.-hydroxy aldehyde as a fundamental building block. Previous methods for the synthesis of such aldehydes have relied principally on aldol addition and allylation reactions and related processes. (Carreira, et al, 1994; Evans, et al., 1996; Evans, et al., 1997; Paterson, et al., 1996; Yamamoto, et al, 1993). However, the focus of the present invention on the carbonyl carbon--.alpha.-carbon bond by way of olefin carbonylation provides a novel approach to catalytic aldol synthesis (FIG. 1A).
These methodologies involve as the unifying theme stereo- and regioselective transition metal-catalyzed carbonylation of alkenes leading to the efficient synthesis of suitably protected/masked 3,5-dihydroxy aldehydes, extremely versatile building blocks for polyol synthesis (FIG. 1B). Focus on carbonylation derives from the observation that carbonylation is one of the most efficient and widely used processes in the chemical industry for the production of carbonyl containing compounds. (Colquhoun, et al, 1991). Thus, the development of carbonylation-based methods for the synthesis of (1,3,5 . . . ) polyols could accrue all the advantages that render carbonylation a feasible industrial scale process. Toward this end, four criteria may be used to evaluate the development of these new synthetic methods. First, the diastereoselectivity should be high (to avoid tedious separations) and, as important, predictable. Second, the reactions should be efficient, providing high yields of the desired products with minimal waste production and minimal use of unwieldy and/or expensive reagents. Third, the reactions should be operationally simple requiring no extraordinary techniques and, ideally, requiring little or no work-up and only simple purification methods. Finally, the usefulness of the methods will be limited if the availability of the requisite starting materials is limited.
The present invention provides the basis for a comprehensive and coherent approach to the synthesis of (1,3,5 . . . ) polyol fragments and the efficient synthesis of relevant targets.